PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness in pediatric patients (below 18 years of age) have not been established. Use of MAVENCLAD is not recommended in pediatric patients because of the risk of malignancies [see Warnings and Precautions (5.1)].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions and potential risks are discussed, or discussed in greater detail, in other sections of the labeling:Malignancies [see Warnings and Precautions (5.1)] Risk of Teratogenicity [see Warnings and Precautions (5.2)] Lymphopenia [see Warnings and Precautions (5.3)] Infections [see Warnings and Precautions (5.4)] Hematologic Toxicity [see Warnings and Precautions (5.5)] Graft-Versus-Host Disease With Blood Transfusion [see Warnings and Precautions (5.6)] Liver Injury [see Warnings and Precautions (5.7)] Hypersensitivity [see Warnings and Precautions (5.8)] Cardiac Failure [see Warnings and Precautions (5.9)] Malignancies [see Warnings and Precautions (5.1)] Risk of Teratogenicity [see Warnings and Precautions (5.2)] Lymphopenia [see Warnings and Precautions (5.3)] Infections [see Warnings and Precautions (5.4)] Hematologic Toxicity [see Warnings and Precautions (5.5)] Graft-Versus-Host Disease With Blood Transfusion [see Warnings and Precautions (5.6)] Liver Injury [see Warnings and Precautions (5.7)] Hypersensitivity [see Warnings and Precautions (5.8)] Cardiac Failure [see Warnings and Precautions (5.9)] Most common adverse reactions (incidence 20%) are upper respiratory tract infection, headache, and lymphopenia. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact EMD Serono at 1-800-283-8088 ext. 5563 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.In the clinical trial program of cladribine in MS, 1,976 patients received cladribine for total of 9,509 patient years. The mean time on study including follow-up was approximately 4.8 years, and approximately 24% of cladribine-treated patients had approximately years of time on study including follow-up. Of these, 923 patients aged 18 to 66 years received MAVENCLAD as monotherapy at cumulative dose of 3.5 mg per kg.Table shows adverse reactions in Study [see Clinical Studies (14)] with an incidence of at least 5% for MAVENCLAD and higher than placebo. The most common (> 20%) adverse reactions reported in Study are upper respiratory tract infection, headache, and lymphopenia.Table 2Adverse Reactions in Study with an Incidence of at Least 5% for MAVENCLAD and Higher than PlaceboMAVENCLAD(N=440)%Placebo(N=435)%Upper respiratory tract infection3832Headache2519Lymphopenia242Nausea109Back pain86Arthralgia and arthritis75Insomnia64Bronchitis53Hypertension53Fever53Depression53. HypersensitivityIn clinical studies, 11% of MAVENCLAD patients had hypersensitivity adverse reactions, compared to 7% of placebo patients [see Warnings and Precautions (5.8)]. AlopeciaAlopecia occurred in 3% of MAVENCLAD-treated patients compared to 1% of placebo patients.. Myelodysplastic SyndromeCases of myelodysplastic syndrome have been reported in patients that had received parenteral cladribine at higher dosage than that approved for MAVENCLAD. These cases occurred several years after treatment.. Herpes MeningoencephalitisFatal herpes meningoencephalitis occurred in one MAVENCLAD-treated patient, at higher dosage and longer duration of therapy than the approved MAVENCLAD dosage and in combination with interferon beta-1a treatment.. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)SJS and TEN are identified risks of parenteral cladribine for the treatment of oncologic indications.. SeizuresIn clinical studies, serious events of seizure occurred in 0.3% of MAVENCLAD-treated patients compared to placebo patients. Serious events included generalized tonic-clonic seizures and status epilepticus. It is unknown whether these events were related to the effects of multiple sclerosis alone, to MAVENCLAD, or to combination of both.

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Pregnancy TestingIn females of reproductive potential, pregnancy should be excluded before the initiation of each treatment course of MAVENCLAD [see Use in Specific Populations (8.1)]. Contraception. FemalesFemales of reproductive potential should prevent pregnancy by use of effective contraception during MAVENCLAD dosing and for at least months after the last dose in each treatment course. It is unknown if MAVENCLAD may reduce the effectiveness of the systemically acting hormonal contraceptives. Women using systemically acting hormonal contraceptives should add barrier method during MAVENCLAD dosing and for at least weeks after the last dose in each treatment course. Women who become pregnant during MAVENCLAD therapy should discontinue treatment [see Warnings and Precautions (5.2) and Drug Interactions (7.7)]. MalesAs cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected. Therefore, male patients of reproductive potential should take precautions to prevent pregnancy of their partner during MAVENCLAD dosing and for at least months after the last dose in each treatment course [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1)].

BOXED WARNING SECTION.

WARNING: MALIGNANCIES AND RISK OF TERATOGENICITY. WARNING: MALIGNANCIES and RISK OF TERATOGENICITYSee full prescribing information for complete boxed warning.oMalignancies MAVENCLAD may increase the risk of malignancy. MAVENCLAD is contraindicated in patients with current malignancy; evaluate the benefits and risks on an individual basis for patients with prior or increased risk of malignancy. (5.1)oRisk of Teratogenicity MAVENCLAD is contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception because of the risk of fetal harm. (5.2). oMalignancies Treatment with MAVENCLAD may increase the risk of malignancy. MAVENCLAD is contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of MAVENCLAD on an individual patient basis. Follow standard cancer screening guidelines in patients treated with MAVENCLAD [see Contraindications (4) and Warnings and Precautions (5.1)].. oRisk of Teratogenicity MAVENCLAD is contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception because of the potential for fetal harm. Malformations and embryolethality occurred in animals. Exclude pregnancy before the start of treatment with MAVENCLAD in females of reproductive potential. Advise females and males of reproductive potential to use effective contraception during MAVENCLAD dosing and for months after the last dose in each treatment course. Stop MAVENCLAD if the patient becomes pregnant [see Contraindications (4), Warnings and Precautions (5.2), and Use in Specific Populations (8.1, 8.3)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn mice administered cladribine (0, 0.1, 1, or 10 mg/kg) by subcutaneous injection intermittently (7 daily doses followed by 21 days of non-dosing per cycle) for 22 months, an increase in Harderian gland tumors (adenoma) was observed at the highest dose tested.. MutagenesisCladribine was negative for mutagenicity in in vitro (reverse mutation in bacteria, CHO/HGPRT mammalian cell) assays.Cladribine was positive for clastogenicity in an in vitro mammalian cell assay, in the absence and presence of metabolic activation, and in an in vivo mouse micronucleus assay.. Impairment of FertilityWhen cladribine (0, 1, 5, 10, or 30 mg/kg/day) was administered by subcutaneous injection to male mice prior to and during mating to untreated females, no effects on fertility were observed. However, an increase in non-motile sperm was observed at the highest dose tested. In female mice, administration of cladribine (0, 1, 2, 4, or mg/kg/day) by subcutaneous injection prior to and during mating to untreated males and continuing to gestation day caused an increase in embryolethality at the highest dose tested.In monkeys administered cladribine (0, 0.15, 0.3, or 1.0 mg/kg) by subcutaneous injection intermittently (7 consecutive daily doses followed by 21 days of non-dosing per cycle) for one year, testicular degeneration was observed at the highest dose tested.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism by which cladribine exerts its therapeutic effects in patients with multiple sclerosis has not been fully elucidated but is thought to involve cytotoxic effects on and lymphocytes through impairment of DNA synthesis, resulting in depletion of lymphocytes.. 12.2 Pharmacodynamics. MAVENCLAD causes dose-dependent reduction in lymphocyte count. The lowest absolute lymphocyte counts occurred approximately to months after the start of each treatment cycle and were lower with each additional treatment cycle. At the end of Year 2, 2% of patients continued to have absolute lymphocyte counts less than 500 cells per microliter. The median time to recovery from lymphocyte counts less than 500 cells per microliter to at least 800 cells per microliter was approximately 28 weeks [see Warnings and Precautions (5.3)].. 12.3 Pharmacokinetics. Cladribine is prodrug that becomes active upon phosphorylation to its 2-chlorodeoxyadenosine triphosphate (Cd-ATP) metabolite.The pharmacokinetic parameters presented below were assessed following oral administration of cladribine 10 mg, unless otherwise specified. The cladribine mean maximum concentration (Cmax) was in the range of 22 to 29 ng/ mL and corresponding mean AUC was in the range of 80 to 101 ngh/mL.The Cmax and AUC of cladribine increased proportionally across dose range from to 20 mg.No accumulation of cladribine concentration in plasma was observed after repeated dosing.. AbsorptionThe bioavailability of cladribine was approximately 40%. Following fasted administration of cladribine, the median time to maximum concentration (Tmax) was 0.5 (range 0.5 to 1.5 hours).. Effect of FoodFollowing administration of cladribine with high fat meal, the geometric mean Cmax decreased by 29% and AUC was unchanged. The Tmax was prolonged to 1.5 hours (range to hours). This difference is not expected to be clinically significant.. DistributionCladribine mean apparent volume of distribution ranges from 480 to 490 liters. The plasma protein binding of cladribine is 20% and is independent of concentration, in vitro.Intracellular concentrations of cladribine and/or its metabolites in human lymphocytes were approximately 30 to 40 times extracellular, in vitro.Cladribine has the potential to penetrate the blood brain barrier. cerebrospinal fluid/plasma concentration ratio of approximately 0.25 was observed in cancer patients.. EliminationCladribine estimated terminal half-life is approximately day. The intracellular half-life of the cladribine phosphorylated metabolites cladribine monophosphate (Cd-AMP) is 15 hours and Cd-ATP is 10 hours. Cladribine estimated median apparent renal clearance is 22.2 liter per hour and non-renal clearance is 23.4 liter per hour.. MetabolismCladribine is prodrug that is phosphorylated to Cd-AMP by deoxycytidine kinase (and also by deoxyguanosine kinase in the mitochondria) in lymphocytes. Cd-AMP is further phosphorylated to cladribine diphosphate (Cd-ADP) and the active moiety Cd-ATP. The dephosphorylation and deactivation of Cd-AMP is catalyzed by cytoplasmic 5-nucleotidase (5-NTase).The metabolism of cladribine in whole blood has not been fully characterized. However, extensive whole blood and negligible hepatic enzyme metabolism was observed, in vitro.. ExcretionAfter administration of 10 mg oral cladribine in MS patients, 28.5 [20] (mean [SD]) percent of the dose was excreted unchanged via the renal route. Renal clearance exceeded the glomerular filtration rate, indicating active renal secretion of cladribine.. Specific PopulationsNo studies have been conducted to evaluate the pharmacokinetics of cladribine in elderly or in patients with renal or hepatic impairment.There were no clinically significant differences in the pharmacokinetics of cladribine based on age (range 18 to 65 years) or gender. The effect of hepatic impairment on the pharmacokinetics of cladribine is unknown.. Patients with Renal ImpairmentRenal clearance of cladribine was shown to be dependent on creatinine clearance (CLCR). No dedicated studies have been conducted in patients with renal impairment, however patients with mild renal impairment (CLCR of 60 mL to below 90 mL per minute) were included in Study 1. pooled pharmacokinetic analysis estimated decrease of 18% in total clearance in typical subject with CLCR of 65 mL per minute leading to an increase in cladribine exposure of 25%. Clinical experience in patients with moderate to severe renal impairment (i.e., CLCR below 60 mL per minute) is limited [see Use in Specific Populations (8.6)]. Drug Interaction Studies. Clinical StudiesNo clinically significant differences in cladribine pharmacokinetics were observed when used concomitantly with pantoprazole or interferon beta-1a.. In Vitro StudiesIt has been reported that lamivudine can inhibit the phosphorylation of cladribine intracellularly. Potential competition for intracellular phosphorylation exists between cladribine and compounds that require intracellular phosphorylation to become active (e.g., lamivudine, zalcitabine, ribavirin, stavudine, and zidovudine).Cytochrome P450 (CYP) Enzymes: Cladribine is not substrate of cytochrome P450 enzymes and does not show significant potential to act as inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Cladribine has no clinically meaningful inductive effect on CYP1A2, CYP2B6 and CYP3A4 enzymes.Transporter Systems: Cladribine is substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), equilibrative nucleoside transporter (ENT1) and concentrative nucleoside transporter (CNT3). Inhibition of BCRP in the gastrointestinal tract may increase the oral bioavailability and systemic exposure of cladribine. Intracellular distribution and renal elimination of cladribine may be altered by potent ENT1, CNT3 transporter inhibitors.. 12.6 Hydroxypropyl Betadex-Related Complex Formation. MAVENCLAD contains hydroxypropyl betadex that may be available for complex formation with the active ingredients of other drugs. Complex formation between free hydroxypropyl betadex, released from the cladribine tablet formulation, and concomitant ibuprofen, furosemide, and gabapentin was observed. Concomitant use with MAVENCLAD may increase the bioavailability of other drugs (especially agents with low solubility), which may increase the risk or severity of adverse reactions [see Dosage and Administration (2.4)].

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The efficacy of MAVENCLAD was demonstrated in 96-week randomized, double-blind, placebo-controlled clinical study in patients with relapsing forms of MS (Study 1; NCT00213135).Patients were required to have at least relapse in the previous 12 months. The median age was 39 years (range 18 to 65) and the female-to-male ratio was approximately 2:1. The mean duration of MS prior to study enrollment was 8.7 years, and the median baseline neurological disability based on Kurtzke Expanded Disability Status Scale (EDSS) score across all treatment groups was 3.0. Over two thirds of the study patients were treatment-naive for drugs used to treat relapsing forms of MS.1,326 patients were randomized to receive either placebo (n 437), or cumulative oral dosage of MAVENCLAD 3.5 mg per kg (n 433) or 5.25 mg per kg body weight (n 456) over the 96-week study period in treatment courses. Patients randomized to the 3.5 mg per kg cumulative dose received first treatment course at Weeks and of the first year and second treatment course at Weeks and of the second year [see Dosage and Administration (2.2)]. Patients randomized to the 5.25 mg per kg cumulative dose received additional treatment at Weeks and 13 of the first year. Higher cumulative doses did not add any clinically meaningful benefit, but were associated with higher incidence in grade lymphopenia or higher (44.9% in the 5.25 mg per kg group vs. 25.6% in the 3.5 mg per kg group). Ninety-two percent of patients treated with MAVENCLAD 3.5 mg per kg and 87% of patients receiving placebo completed the full 96 weeks of the study.The primary outcome of Study was the annualized relapse rate (ARR). Additional outcome measures included the proportion of patients with confirmed disability progression, the time to first qualifying relapse, the mean number of MRI T1 Gadolinium-enhancing (Gd+) lesions, and new or enlarging MRI T2 hyperintense lesions. Disability progression was measured in terms of 3-month sustained change in EDSS score of at least one point, if baseline EDSS score was between 0.5 and 4.5 inclusively, or at least 1.5 points if the baseline EDSS score was 0, or at least 0.5 point if the baseline EDSS score was at least 5, over period of at least months.MAVENCLAD 3.5 mg per kg significantly lowered the annualized relapse rate. The results from Study are presented in Table 4.Table 4Clinical Outcomes in Study (96 Weeks) Primary and Secondary EndpointsMAVENCLADPlaceboEndpointsCumulative Dose 3.5 mg per kg(n 433)(n 437)HR: Hazard RatioClinical Endpoints Annualized relapse rate (ARR)0.14p 0.001 compared to placebo 0.33 Relative reduction in ARR58% Proportion of patients without relapse81%nominal < 0.05 compared to placebo 63% Time to 3-month confirmed EDSS progression, HR0.67 Proportion of patients with 3-month EDSS progression13%19%MRI Endpoints Median Number of Active T1 Gd+ Lesions0 0.33 Median Number of Active T2 Lesions0 0.67.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. MAVENCLAD is contraindicated:in patients with current malignancy [see Warnings and Precautions (5.1)]. in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception during MAVENCLAD dosing and for months after the last dose in each treatment course. May cause fetal harm [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3)].in patients infected with the human immunodeficiency virus (HIV) [see Warnings and Precautions (5.4)]. in patients with active chronic infections (e.g., hepatitis or tuberculosis) [see Warnings and Precautions (5.4)]. in patients with history of hypersensitivity to cladribine [see Warnings and Precautions (5.8)]. in women intending to breastfeed on MAVENCLAD treatment day and for 10 days after the last dose [see Use in Specific Populations (8.2)]. in patients with current malignancy [see Warnings and Precautions (5.1)]. in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception during MAVENCLAD dosing and for months after the last dose in each treatment course. May cause fetal harm [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3)].. in patients infected with the human immunodeficiency virus (HIV) [see Warnings and Precautions (5.4)]. in patients with active chronic infections (e.g., hepatitis or tuberculosis) [see Warnings and Precautions (5.4)]. in patients with history of hypersensitivity to cladribine [see Warnings and Precautions (5.8)]. in women intending to breastfeed on MAVENCLAD treatment day and for 10 days after the last dose [see Use in Specific Populations (8.2)]. Patients with current malignancy. (4)Pregnant women, and women and men of reproductive potential who do not plan to use effective contraception during MAVENCLAD dosing and for months after the last dose in each treatment course. (4, 8.3)HIV infection. (4)Active chronic infections (e.g., hepatitis or tuberculosis). (4)History of hypersensitivity to cladribine. (4, 5.8)Women intending to breastfeed on MAVENCLAD treatment day and for 10 days after the last dose. (4, 8.2). Patients with current malignancy. (4). Pregnant women, and women and men of reproductive potential who do not plan to use effective contraception during MAVENCLAD dosing and for months after the last dose in each treatment course. (4, 8.3). HIV infection. (4). Active chronic infections (e.g., hepatitis or tuberculosis). (4). History of hypersensitivity to cladribine. (4, 5.8). Women intending to breastfeed on MAVENCLAD treatment day and for 10 days after the last dose. (4, 8.2).

DESCRIPTION SECTION.

11 DESCRIPTION. MAVENCLAD contains the nucleoside metabolic inhibitor cladribine, which is white or almost white, non-hydroscopic, crystalline powder with the molecular formula C10H12ClN5O3 and molecular weight 285.69. It differs in structure from the naturally occurring nucleoside, deoxyadenosine, by the substitution of chlorine for hydrogen in the 2-position of the purine ring.The chemical name of cladribine is 2-chloro-2-deoxy-adenosine. The structural formula is shown below:Cladribine is stable at slightly basic and at neutral pH. The main degradation pathway is hydrolysis and at acidic pH significant decomposition occurs with time. The ionization behavior of the molecule over the pH range to 12 is characterized by single pKa of approximately 1.21.MAVENCLAD is provided as 10 mg tablets for oral use. Each MAVENCLAD 10 mg tablet contains cladribine as an active ingredient and hydroxypropyl betadex, magnesium stearate, and sorbitol as inactive ingredients.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Assessments are required prior to starting each MAVENCLAD treatment course. (2.1)Cumulative dosage of 3.5 mg/kg administered orally and divided into treatment courses (1.75 mg/kg per treatment course). Each treatment course is divided into treatment cycles. (2.2)MAVENCLAD is cytotoxic drug. (2.4)Separate administration from any other oral drug by at least hours. (2.4). Assessments are required prior to starting each MAVENCLAD treatment course. (2.1). Cumulative dosage of 3.5 mg/kg administered orally and divided into treatment courses (1.75 mg/kg per treatment course). Each treatment course is divided into treatment cycles. (2.2). MAVENCLAD is cytotoxic drug. (2.4). Separate administration from any other oral drug by at least hours. (2.4). 2.1Assessments Prior to Starting Each MAVENCLAD Treatment Course. Cancer ScreeningFollow standard cancer screening guidelines because of the risk of malignancies [see Boxed Warning and Warnings and Precautions (5.1)].. PregnancyExclude pregnancy prior to treatment with MAVENCLAD in females of reproductive potential [see Contraindications (4), Warnings and Precautions (5.2), and Use in Specific Populations (8.1, 8.3)].. Complete Blood Count (CBC)Obtain CBC with differential including lymphocyte count [see Dosage and Administration (2.5) and Warnings and Precautions (5.3)]. Lymphocytes must be:within normal limits before initiating the first treatment courseat least 800 cells per microliter before initiating the second treatment courseIf necessary, delay the second treatment course for up to months to allow for recovery of lymphocytes to at least 800 cells per microliter. If this recovery takes more than months, the patient should not receive further treatment with MAVENCLAD.. within normal limits before initiating the first treatment course. at least 800 cells per microliter before initiating the second treatment course. Infections [see Warnings and Precautions (5.4)]Exclude HIV infection.Perform tuberculosis screening.Screen for hepatitis and C.Evaluate for acute infection. Consider delay in MAVENCLAD treatment until any acute infection is fully controlled.Vaccination of patients who are antibody-negative for varicella zoster virus is recommended prior to initiation of MAVENCLAD.Administer all immunizations according to immunization guidelines prior to starting MAVENCLAD. Administer live-attenuated or live vaccines at least to weeks prior to starting MAVENCLAD.Obtain baseline (within months) magnetic resonance imaging prior to the first treatment course because of the risk of progressive multifocal leukoencephalopathy (PML).. Exclude HIV infection.. Perform tuberculosis screening.. Screen for hepatitis and C.. Evaluate for acute infection. Consider delay in MAVENCLAD treatment until any acute infection is fully controlled.. Vaccination of patients who are antibody-negative for varicella zoster virus is recommended prior to initiation of MAVENCLAD.. Administer all immunizations according to immunization guidelines prior to starting MAVENCLAD. Administer live-attenuated or live vaccines at least to weeks prior to starting MAVENCLAD.. Obtain baseline (within months) magnetic resonance imaging prior to the first treatment course because of the risk of progressive multifocal leukoencephalopathy (PML).. Liver InjuryObtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels [see Warnings and Precautions (5.7)]. 2.2Recommended Dosage. The recommended cumulative dosage of MAVENCLAD is 3.5 mg per kg body weight administered orally and divided into yearly treatment courses (1.75 mg per kg per treatment course) (see Table 1). Each treatment course is divided into treatment cycles:. Administration of First Treatment CourseFirst Course/First Cycle: start any time.First Course/Second Cycle: administer 23 to 27 days after the last dose of First Course/First Cycle.. First Course/First Cycle: start any time.. First Course/Second Cycle: administer 23 to 27 days after the last dose of First Course/First Cycle.. Administration of Second Treatment CourseSecond Course/First Cycle: administer at least 43 weeks after the last dose of First Course/Second Cycle.Second Course/Second Cycle: administer 23 to 27 days after the last dose of Second Course/First Cycle.Table 1Dose of MAVENCLAD per Cycle by Patient Weight in Each Treatment CourseWeight RangeDose in mg (Number of 10 mg Tablets) per CyclekgFirst CycleSecond Cycle40The use of MAVENCLAD in patients weighing less than 40 kg has not been investigated. to less than 5040 mg (4 tablets)40 mg (4 tablets)50 to less than 6050 mg (5 tablets)50 mg (5 tablets)60 to less than 7060 mg (6 tablets)60 mg (6 tablets)70 to less than 8070 mg (7 tablets)70 mg (7 tablets)80 to less than 9080 mg (8 tablets)70 mg (7 tablets)90 to less than 10090 mg (9 tablets)80 mg (8 tablets)100 to less than 110100 mg (10 tablets)90 mg (9 tablets)110 and above100 mg (10 tablets)100 mg (10 tablets)Administer the cycle dosage as or tablets once daily over or consecutive days [see How Supplied/Storage and Handling (16.1)]. Do not administer more than tablets daily.Following the administration of treatment courses, do not administer additional MAVENCLAD treatment during the next years. Treatment during these years may further increase the risk of malignancy [see Warnings and Precautions (5.1)]. The safety and efficacy of reinitiating MAVENCLAD more than years after completing treatment courses has not been studied.. Second Course/First Cycle: administer at least 43 weeks after the last dose of First Course/Second Cycle.. Second Course/Second Cycle: administer 23 to 27 days after the last dose of Second Course/First Cycle.. 2.3Missed Dose. If dose is missed, patients should not take double or extra doses.If dose is not taken on the scheduled day, then the patient must take the missed dose on the following day and extend the number of days in that treatment cycle. If two consecutive doses are missed, the treatment cycle is extended by days.. 2.4Administration. MAVENCLAD tablets are taken orally, with water, and swallowed whole without chewing. MAVENCLAD can be taken with or without food.Separate administration of MAVENCLAD and any other oral drugs by at least hours during the to day MAVENCLAD treatment cycles [see Clinical Pharmacology (12.6)]. MAVENCLAD is cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)]. MAVENCLAD is an uncoated tablet and must be swallowed immediately once removed from the blister. If tablet is left on surface, or if broken or fragmented tablet is released from the blister, the area must be thoroughly washed with water.The patients hands must be dry when handling the tablets and washed thoroughly afterwards. Avoid prolonged contact with skin.. 2.5Laboratory Testing and Monitoring to Assess Safety. Cancer ScreeningFollow standard cancer screening guidelines in patients treated with MAVENCLAD [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)].. Complete Blood CountObtain complete blood count (CBC) with differential including lymphocyte count:before initiating the first treatment course of MAVENCLADbefore initiating the second treatment course of MAVENCLAD2 and months after start of treatment in each treatment course; if the lymphocyte count at month is below 200 cells per microliter, monitor monthly until month 6. See Warnings and Precautions (5.3, 5.4) for instructions based on the patients lymphocyte counts and clinical status (e.g., infections). Hold MAVENCLAD therapy if the lymphocyte count is below 200 cells per microliter periodically thereafter and when clinically indicated [see Warnings and Precautions (5.5)] before initiating the first treatment course of MAVENCLAD. before initiating the second treatment course of MAVENCLAD. and months after start of treatment in each treatment course; if the lymphocyte count at month is below 200 cells per microliter, monitor monthly until month 6. See Warnings and Precautions (5.3, 5.4) for instructions based on the patients lymphocyte counts and clinical status (e.g., infections). Hold MAVENCLAD therapy if the lymphocyte count is below 200 cells per microliter. periodically thereafter and when clinically indicated [see Warnings and Precautions (5.5)] 2.6Recommended Concomitant Medication. Herpes ProphylaxisAdminister anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter [see Warnings and Precautions (5.4)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. MAVENCLAD is available as 10 mg tablets. The tablets are uncoated, white, round, biconvex, and engraved with C on one side and 10 on the other side.. Tablets: 10 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table 3Drug Interactions with MAVENCLAD7.1 Immunomodulatory, Immunosuppressive, or Myelosuppressive DrugsClinical ImpactConcomitant use of MAVENCLAD with immunomodulatory, immunosuppressive, or myelosuppressive drugs may increase the risk of adverse reactions because of the additive effects on the immune system [see Warnings and Precautions (5.4)].Prevention or ManagementConcomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute short-term therapy with corticosteroids can be administered.In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of MAVENCLAD.7.2 Interferon-BetaClinical ImpactConcomitant use of MAVENCLAD with interferon-beta did not change the exposure of cladribine to clinically significant effect; however, lymphopenia risk may be increased [see Warnings and Precautions (5.3)]. Prevention or ManagementConcomitant use is not recommended.7.3 Hematotoxic DrugsClinical ImpactConcomitant use of MAVENCLAD with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematological effects [see Warnings and Precautions (5.5)]. Prevention or ManagementMonitor hematological parameters.7.4 Antiviral and Antiretroviral DrugsClinical ImpactCompounds that require intracellular phosphorylation to become active (e.g., lamivudine, zalcitabine, ribavirin, stavudine, and zidovudine) could interfere with the intracellular phosphorylation and activity of cladribine.Prevention or ManagementAvoid concomitant use. 7.5 Potent ENT, CNT and BCRP Transporter InhibitorsClinical ImpactCladribine is substrate of breast cancer resistance protein (BCRP), equilibrative nucleoside (ENT1), and concentrative nucleoside (CNT3) transport proteins. The bioavailability, intracellular distribution, and renal elimination of cladribine may be altered by potent ENT1, CNT3, and BCRP transporter inhibitors.Prevention or ManagementAvoid co-administration of potent ENT1, CNT3, or BCRP transporter inhibitors (e.g., ritonavir, eltrombopag, curcumin, cyclosporine, dilazep, nifedipine, nimodipine, cilostazol, sulindac, dipyridamole, or reserpine) during the to day MAVENCLAD treatment cycles. If this is not possible, consider selection of alternative concomitant drugs with no or minimal ENT1, CNT3, or BCRP transporter inhibiting properties. If this is not possible, dose reduction to the minimum mandatory dose of drugs containing these compounds, separation in the timing of administration, and careful patient monitoring is recommended.7.6 Potent BCRP and P-gp Transporter InducersClinical ImpactPossible decrease in cladribine exposure if potent BCRP or P-gp transporter inducers are co-administered.Prevention or ManagementConsider possible decrease in cladribine efficacy if potent BCRP (e.g., corticosteroids) or P-gp (e.g., rifampicin, St. Johns Wort) transporter inducers are co-administered.7.7 Hormonal ContraceptivesClinical ImpactIt is currently unknown whether MAVENCLAD may reduce the effectiveness of systemically acting hormonal contraceptives.Prevention or ManagementWomen using systemically acting hormonal contraceptives should add barrier method during MAVENCLAD dosing and for at least weeks after the last dose in each treatment course.. Immunosuppressive drugs: Consider overlapping effects on immune system, when used sequentially. Concomitant use not recommended. (7.1)Hematotoxic drugs: Monitor patients for additive effects on the hematological profile. (7.3)Antiviral and antiretroviral drugs: Avoid concomitant use. (7.4)BCRP or ENT/CNT inhibitors: May alter bioavailability of cladribine. Avoid concomitant use. (7.5). Immunosuppressive drugs: Consider overlapping effects on immune system, when used sequentially. Concomitant use not recommended. (7.1). Hematotoxic drugs: Monitor patients for additive effects on the hematological profile. (7.3). Antiviral and antiretroviral drugs: Avoid concomitant use. (7.4). BCRP or ENT/CNT inhibitors: May alter bioavailability of cladribine. Avoid concomitant use. (7.5).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies with MAVENCLAD did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution is recommended when MAVENCLAD is used in elderly patients, taking into account the potential greater frequency of decreased hepatic, renal, or cardiac function, concomitant diseases, and other drug therapy.

HEPATIC IMPAIRMENT SUBSECTION.

8.7Patients with Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics of cladribine is unknown [see Clinical Pharmacology (12.3)]. No dosage adjustment is recommended in patients with mild hepatic impairment. MAVENCLAD is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh score greater than 6) [see Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. MAVENCLAD tablets, 10 mg, are uncoated, white, round, biconvex, and engraved with C on one side and 10 on the other side. Each tablet is packaged in child-resistant day pack containing one or two tablets in blister card.Dispense one box for each treatment cycle with Medication Guide [see Dosage and Administration (2.2)]. PresentationsNDC 44087-4000-4Box of tablets: Four day packs each containing one tablet.NDC 44087-4000-5Box of tablets: Five day packs each containing one tablet.NDC 44087-4000-6Box of tablets: One day pack containing two tablets. Four day packs each containing one tablet.NDC 44087-4000-7Box of tablets: Two day packs each containing two tablets. Three day packs each containing one tablet.NDC 44087-4000-8Box of tablets: Three day packs each containing two tablets. Two day packs each containing one tablet.NDC 44087-4000-9Box of tablets: Four day packs each containing two tablets. One day pack containing one tablet.NDC 44087-4000-0Box of 10 tablets: Five day packs each containing two tablets.. 16.2Storage and Handling. Store at controlled room temperature, 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Store in original package in order to protect from moisture.MAVENCLAD is cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. MAVENCLAD is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, use of MAVENCLAD is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS [see Warnings and Precautions (5)]. MAVENCLAD is purine antimetabolite indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, use of MAVENCLAD is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS [see Warnings and Precautions (5)]. (1)Limitations of UseMAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile [see Warnings and Precautions (5)]. (1). Limitations of UseMAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile [see Warnings and Precautions (5)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. MalignanciesInform patients that MAVENCLAD may increase their risk of malignancies. Instruct patients to follow standard cancer screening guidelines [see Dosage and Administration (2) and Warnings and Precautions (5.1)]. Risk of TeratogenicityInform patients that MAVENCLAD may cause fetal harm. Discuss with women of childbearing age whether they are pregnant, might be pregnant, or are trying to become pregnant. Before initiating each treatment course, inform patients about the potential risk to the fetus, if female patients or partners of male patients get pregnant during MAVENCLAD dosing or within months after the last dose in each treatment course [see Warnings and Precautions (5.2) and Use in Specific Populations (8.1, 8.3)]. Instruct female patients of childbearing potential to use effective contraception during MAVENCLAD dosing and for at least months after the last dose in each treatment course to avoid pregnancy. Advise women using systemically acting hormonal contraceptives to add barrier method during MAVENCLAD dosing and for at least weeks after the last dose in each treatment course because MAVENCLAD may reduce the effectiveness of the hormonal contraceptive [see Drug Interactions (7.7)].Instruct male patients to take precautions to prevent pregnancy of their partner during MAVENCLAD dosing and for at least months after the last dose in each treatment course.Advise patients that female patients or partners of male patients who get pregnant immediately inform their healthcare provider.. LactationInform women that they cannot breastfeed on MAVENCLAD treatment day and for 10 days after the last dose [see Use in Specific Populations (8.2)]. Lymphopenia and Other Hematologic ToxicityInform patients that MAVENCLAD may decrease lymphocyte counts and may also decrease counts of other blood cells. blood test should be obtained before starting treatment course, and months after start of treatment in each treatment course, periodically thereafter, and when clinically needed. Advise patients to keep all appointments for lymphocyte monitoring during and after MAVENCLAD treatment [see Dosage and Administration (2.5) and Warnings and Precautions (5.3, 5.5)]. InfectionsInform patients that use of MAVENCLAD may increase the risk of infections. Instruct patients to notify their healthcare provider promptly if fever or other signs of infection such as aching, painful muscles, headache, generally feeling unwell or loss of appetite occur while on therapy or after course of treatment [see Warnings and Precautions (5.4)].Advise patients that PML has happened with parenteral cladribine used in oncologic indications. Inform the patient that PML is characterized by progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes [see Warnings and Precautions (5.4)]. Liver InjuryInform patients that MAVENCLAD may cause liver injury. Instruct patients treated with MAVENCLAD to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. blood test should be obtained prior to each treatment course with MAVENCLAD and as clinically indicated thereafter [see Warnings and Precautions (5.7)]. HypersensitivityAdvise patients to seek immediate medical attention if they experience any symptoms of serious or severe hypersensitivity reactions, including skin reactions [see Warnings and Precautions (5.8)]. Cardiac FailureAdvise patients that MAVENCLAD may cause cardiac failure. Instruct patients to seek medical advice if they experience symptoms of cardiac failure (e.g., shortness of breath, rapid or irregular heartbeat, swelling) [see Warnings and Precautions (5.9)]. Treatment Handling and AdministrationInstruct patients that MAVENCLAD is cytotoxic drug and to use care when handling MAVENCLAD tablets, limit direct skin contact with the tablets, and wash exposed areas thoroughly. Advise patients to keep the tablets in the original package until just prior to each scheduled dose and consult their pharmacist on the proper disposal of unused tablets [see Dosage and Administration (2.4) and How Supplied/Storage and Handling (16.2)].

LACTATION SECTION.

8.2 Lactation. Risk SummaryMAVENCLAD is contraindicated in breastfeeding women because of the potential for serious adverse reactions in breastfed infants [see Contraindications (4) and Warnings and Precautions (5)]. Advise women not to breastfeed during dosing with MAVENCLAD and for 10 days after the last dose.There are no data on the presence of cladribine in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The mechanism by which cladribine exerts its therapeutic effects in patients with multiple sclerosis has not been fully elucidated but is thought to involve cytotoxic effects on and lymphocytes through impairment of DNA synthesis, resulting in depletion of lymphocytes.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisIn mice administered cladribine (0, 0.1, 1, or 10 mg/kg) by subcutaneous injection intermittently (7 daily doses followed by 21 days of non-dosing per cycle) for 22 months, an increase in Harderian gland tumors (adenoma) was observed at the highest dose tested.. MutagenesisCladribine was negative for mutagenicity in in vitro (reverse mutation in bacteria, CHO/HGPRT mammalian cell) assays.Cladribine was positive for clastogenicity in an in vitro mammalian cell assay, in the absence and presence of metabolic activation, and in an in vivo mouse micronucleus assay.. Impairment of FertilityWhen cladribine (0, 1, 5, 10, or 30 mg/kg/day) was administered by subcutaneous injection to male mice prior to and during mating to untreated females, no effects on fertility were observed. However, an increase in non-motile sperm was observed at the highest dose tested. In female mice, administration of cladribine (0, 1, 2, 4, or mg/kg/day) by subcutaneous injection prior to and during mating to untreated males and continuing to gestation day caused an increase in embryolethality at the highest dose tested.In monkeys administered cladribine (0, 0.15, 0.3, or 1.0 mg/kg) by subcutaneous injection intermittently (7 consecutive daily doses followed by 21 days of non-dosing per cycle) for one year, testicular degeneration was observed at the highest dose tested.

OVERDOSAGE SECTION.

10 OVERDOSAGE. There is no experience with overdose of MAVENCLAD. Lymphopenia is known to be dose-dependent. Particularly close monitoring of hematological parameters is recommended in patients who have been exposed to an overdose of MAVENCLAD [see Warnings and Precautions (5.3, 5.5)]. There is no known specific antidote to an overdose of MAVENCLAD. Treatment consists of careful observation and initiation of appropriate supportive measures. Discontinuation of MAVENCLAD may need to be considered. Because of the rapid and extensive intracellular and tissue distribution, hemodialysis is unlikely to eliminate cladribine to significant extent.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 4 Tablet Blister Pack Carton. NDC 44087-4000-4MAVENCLAD(R) (cladribine) tablets10 mg per tabletContents:4 tablets: Four child-resistant day packs eachcontaining one 10 mg tablet in blister card.Dosage and Administration:Based on body weight. For oral administration.See enclosed Prescribing Information and MedicationGuide.Separate ingestion of other oral medicines by atleast hours before and after taking MAVENCLAD.Cytotoxic Agent:Handle tablets as directed.Dispense with enclosed Medication Guide.Rx Only4 TabletsEMDSERONO. PRINCIPAL DISPLAY PANEL 4 Tablet Blister Pack Carton.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. MAVENCLAD causes dose-dependent reduction in lymphocyte count. The lowest absolute lymphocyte counts occurred approximately to months after the start of each treatment cycle and were lower with each additional treatment cycle. At the end of Year 2, 2% of patients continued to have absolute lymphocyte counts less than 500 cells per microliter. The median time to recovery from lymphocyte counts less than 500 cells per microliter to at least 800 cells per microliter was approximately 28 weeks [see Warnings and Precautions (5.3)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Cladribine is prodrug that becomes active upon phosphorylation to its 2-chlorodeoxyadenosine triphosphate (Cd-ATP) metabolite.The pharmacokinetic parameters presented below were assessed following oral administration of cladribine 10 mg, unless otherwise specified. The cladribine mean maximum concentration (Cmax) was in the range of 22 to 29 ng/ mL and corresponding mean AUC was in the range of 80 to 101 ngh/mL.The Cmax and AUC of cladribine increased proportionally across dose range from to 20 mg.No accumulation of cladribine concentration in plasma was observed after repeated dosing.. AbsorptionThe bioavailability of cladribine was approximately 40%. Following fasted administration of cladribine, the median time to maximum concentration (Tmax) was 0.5 (range 0.5 to 1.5 hours).. Effect of FoodFollowing administration of cladribine with high fat meal, the geometric mean Cmax decreased by 29% and AUC was unchanged. The Tmax was prolonged to 1.5 hours (range to hours). This difference is not expected to be clinically significant.. DistributionCladribine mean apparent volume of distribution ranges from 480 to 490 liters. The plasma protein binding of cladribine is 20% and is independent of concentration, in vitro.Intracellular concentrations of cladribine and/or its metabolites in human lymphocytes were approximately 30 to 40 times extracellular, in vitro.Cladribine has the potential to penetrate the blood brain barrier. cerebrospinal fluid/plasma concentration ratio of approximately 0.25 was observed in cancer patients.. EliminationCladribine estimated terminal half-life is approximately day. The intracellular half-life of the cladribine phosphorylated metabolites cladribine monophosphate (Cd-AMP) is 15 hours and Cd-ATP is 10 hours. Cladribine estimated median apparent renal clearance is 22.2 liter per hour and non-renal clearance is 23.4 liter per hour.. MetabolismCladribine is prodrug that is phosphorylated to Cd-AMP by deoxycytidine kinase (and also by deoxyguanosine kinase in the mitochondria) in lymphocytes. Cd-AMP is further phosphorylated to cladribine diphosphate (Cd-ADP) and the active moiety Cd-ATP. The dephosphorylation and deactivation of Cd-AMP is catalyzed by cytoplasmic 5-nucleotidase (5-NTase).The metabolism of cladribine in whole blood has not been fully characterized. However, extensive whole blood and negligible hepatic enzyme metabolism was observed, in vitro.. ExcretionAfter administration of 10 mg oral cladribine in MS patients, 28.5 [20] (mean [SD]) percent of the dose was excreted unchanged via the renal route. Renal clearance exceeded the glomerular filtration rate, indicating active renal secretion of cladribine.. Specific PopulationsNo studies have been conducted to evaluate the pharmacokinetics of cladribine in elderly or in patients with renal or hepatic impairment.There were no clinically significant differences in the pharmacokinetics of cladribine based on age (range 18 to 65 years) or gender. The effect of hepatic impairment on the pharmacokinetics of cladribine is unknown.. Patients with Renal ImpairmentRenal clearance of cladribine was shown to be dependent on creatinine clearance (CLCR). No dedicated studies have been conducted in patients with renal impairment, however patients with mild renal impairment (CLCR of 60 mL to below 90 mL per minute) were included in Study 1. pooled pharmacokinetic analysis estimated decrease of 18% in total clearance in typical subject with CLCR of 65 mL per minute leading to an increase in cladribine exposure of 25%. Clinical experience in patients with moderate to severe renal impairment (i.e., CLCR below 60 mL per minute) is limited [see Use in Specific Populations (8.6)]. Drug Interaction Studies. Clinical StudiesNo clinically significant differences in cladribine pharmacokinetics were observed when used concomitantly with pantoprazole or interferon beta-1a.. In Vitro StudiesIt has been reported that lamivudine can inhibit the phosphorylation of cladribine intracellularly. Potential competition for intracellular phosphorylation exists between cladribine and compounds that require intracellular phosphorylation to become active (e.g., lamivudine, zalcitabine, ribavirin, stavudine, and zidovudine).Cytochrome P450 (CYP) Enzymes: Cladribine is not substrate of cytochrome P450 enzymes and does not show significant potential to act as inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Cladribine has no clinically meaningful inductive effect on CYP1A2, CYP2B6 and CYP3A4 enzymes.Transporter Systems: Cladribine is substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), equilibrative nucleoside transporter (ENT1) and concentrative nucleoside transporter (CNT3). Inhibition of BCRP in the gastrointestinal tract may increase the oral bioavailability and systemic exposure of cladribine. Intracellular distribution and renal elimination of cladribine may be altered by potent ENT1, CNT3 transporter inhibitors.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryMAVENCLAD is contraindicated in pregnant women and in females and males of reproductive potential who do not plan to use effective contraception. There are no adequate data on the developmental risk associated with use of MAVENCLAD in pregnant women. Cladribine was embryolethal when administered to pregnant mice and produced malformations in mice and rabbits [see Data]. The observed developmental effects are consistent with the effects of cladribine on DNA [see Contraindications (4) and Warnings and Precautions (5.2)]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.. Data. Animal DataWhen cladribine was administered intravenously (0, 0.5, 1.5, or mg/kg/day) to pregnant mice during the period of organogenesis, fetal growth retardation and malformations (including exencephaly and cleft palate) and embryofetal death were observed at the highest dose tested. An increase in skeletal variations was observed at all but the lowest dose tested. There was no evidence of maternal toxicity.When cladribine was administered intravenously (0, 0.3, 1, and mg/kg/day) to pregnant rabbits during the period of organogenesis, fetal growth retardation and high incidence of craniofacial and limb malformations were observed at the highest dose tested, in the absence of maternal toxicity.When cladribine was administered intravenously (0, 0.5, 1.5, or 3.0 mg/kg/day) to mice throughout pregnancy and lactation, skeletal anomalies and embryolethality were observed at all but the lowest dose tested.

REFERENCES SECTION.

15 REFERENCES. 1OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.. 1OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

RENAL IMPAIRMENT SUBSECTION.

8.6Patients with Renal Impairment. The concentration of cladribine is predicted to increase in patients with renal impairment [see Clinical Pharmacology (12.3)]. No dosage adjustment is recommended in patients with mild renal impairment (creatinine clearance 60 to 89 mL per minute). MAVENCLAD is not recommended in patients with moderate to severe renal impairment (creatinine clearance below 60 mL per minute) [see Clinical Pharmacology (12.3)].

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Issued: 3/2019MEDICATION GUIDEMAVENCLAD(R) (MAY-ven-klad)(cladribine)tablets, for oral useWhat is the most important information should know about MAVENCLADMAVENCLAD can cause serious side effects, including:Risk of cancer (malignancies). Treatment with MAVENCLAD may increase your risk of developing cancer. Talk to your healthcare provider about your risk of developing cancer if you receive MAVENCLAD. You should follow your healthcare provider instructions about screening for cancer.MAVENCLAD may cause birth defects if used during pregnancy. Females must not be pregnant when they start treatment with MAVENCLAD or become pregnant during MAVENCLAD dosing and within months after the last dose of each yearly treatment course. Stop your treatment with MAVENCLAD and call your healthcare provider right away if you become pregnant during treatment with MAVENCLAD.For females who are able to become pregnant:Your healthcare provider should order pregnancy test for you before you begin your first and second yearly treatment course of MAVENCLAD to make sure that you are not pregnant. Your healthcare provider will decide when to do the test.Use effective birth control (contraception) on the days on which you take MAVENCLAD and for at least months after the last dose of each yearly treatment course.Talk to your healthcare provider if you use oral contraceptives (the pill).You should use second method of birth control on the days on which you take MAVENCLAD and for at least weeks after your last dose of each yearly treatment course. For males with female partners who are able to become pregnant:Use effective birth control (contraception) during the days on which you take MAVENCLAD and for at least months after the last dose of each yearly treatment course. What is MAVENCLADMAVENCLAD is prescription medicine used to treat relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, MAVENCLAD is generally used in people who have tried another MS medicine that they could not tolerate or that has not worked well enough.MAVENCLAD is not recommended for use in people with clinically isolated syndrome (CIS).It is not known if MAVENCLAD is safe and effective in children under 18 years of age.Do not take MAVENCLAD if you:have cancer (malignancy).are pregnant, plan to become pregnant, or are woman of childbearing age or man able to father child and you are not using birth control. See What is the most important information should know about MAVENCLADare human immunodeficiency virus (HIV) positive.have active infections, including tuberculosis (TB), hepatitis or C.are allergic to cladribine.are breastfeeding. See Before you take MAVENCLAD, tell your healthcare provider about all of your medical conditions, including if you:Before you take MAVENCLAD, tell your healthcare provider about all of your medical conditions, including if you:think you have an infection.have heart failure.have liver or kidney problems.have taken, take, or plan to take medicines that affect your immune system or your blood cells, or other treatments for MS. Certain medicines can increase your risk of getting an infection.have had recent vaccination or are scheduled to receive any vaccinations. You should not receive live or live-attenuated vaccines within the to weeks preceding your treatment with MAVENCLAD. You should not receive these types of vaccines during your treatment with MAVENCLAD and until your healthcare provider tells you that your immune system is no longer weakened.have or have had cancer.are breastfeeding or plan to breastfeed. It is not known if MAVENCLAD passes into your breast milk. Do not breastfeed on the days, on which you take MAVENCLAD, and for 10 days after the last dose. See Do not take MAVENCLAD if you:Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should take MAVENCLADMAVENCLAD is given as two yearly treatment courses.Each yearly treatment course consists of treatment weeks (also called cycles) that will be about month apart. Your healthcare provider will tell you when you have to start your treatment weeks and how many tablets per week you need, depending on your weight. Each treatment week is or days.Your pharmacist will dispense carton of MAVENCLAD for each treatment week. The prescribed number of tablets per day are provided in child resistant day packs.Take MAVENCLAD exactly as your healthcare provider tells you. Do not change your dose or stop taking MAVENCLAD unless your healthcare provider tells you to.Take MAVENCLAD with water and swallow whole without chewing. MAVENCLAD can be taken with or without food.Swallow MAVENCLAD right away after opening the blister pack.Your hands must be dry when handling MAVENCLAD and washed well with water afterwards.Limit contact with your skin. Avoid touching your nose, eyes and other parts of the body. If you get MAVENCLAD on your skin or on any surface, wash it right away with water.Take MAVENCLAD at least hours apart from other medicines taken by mouth during the 4- to 5-day MAVENCLAD treatment week.If you miss dose, take it as soon as you remember on the same day. If the whole day passes before you remember, take your missed dose the next day. Do not take doses at the same time. Instead, you will extend the number of days in that treatment week.Your healthcare provider will continue to monitor your health during the yearly treatment courses, and for at least another years during which you do not need to take MAVENCLAD. It is not known if MAVENCLAD is safe and effective in people who restart MAVENCLAD treatment more than years after completing yearly treatment courses.What are the possible side effects of MAVENCLADMAVENCLAD can cause serious side effects, including:See What is the most important information should know about MAVENCLAD low blood cell counts. Low blood cell counts have happened and can increase your risk of infections during your treatment with MAVENCLAD. Your healthcare provider will do blood tests before you start treatment with MAVENCLAD, during your treatment with MAVENCLAD, and afterward, as needed.serious infections such as:TB, hepatitis or C, and shingles (herpes zoster). Fatal cases of TB and hepatitis have happened with cladribine during clinical studies. Tell your healthcare provider right away if you get any symptoms of the following infection related problems or if any of the symptoms get worse, including:feveraching painful musclesheadachefeeling of being generally unwellloss of appetiteburning, tingling, numbness or itchiness of the skin in the affected areaskin blotches, blistered rash and severe painprogressive multifocal leukoencephalopathy (PML). PML is rare brain infection that usually leads to death or severe disability. Although PML has not been seen in MS patients taking MAVENCLAD, it may happen in people with weakened immune systems. Symptoms of PML get worse over days to weeks. Call your healthcare provider right away if you have any new or worsening neurologic signs or symptoms of PML, that have lasted several days, including:weakness on side of your bodyloss of coordination in your arms and legsdecreased strengthproblems with balancechanges in your visionchanges in your thinking or memoryconfusionchanges in your personalityliver problems. MAVENCLAD may cause liver problems. Your healthcare provider should do blood tests to check your liver before you start taking MAVENCLAD. Call your healthcare provider right away if you have any of the following symptoms of liver problems:nauseavomitingstomach paintirednessloss of appetiteyour skin or the whites or your eyes turn yellowdark urineallergic reactions (hypersensitivities). MAVENCLAD can cause serious allergic reactions. Stop your treatment with MAVENCLAD and go to the closest emergency room for medical help right away if you have any signs or symptoms of allergic reactions. Symptoms of an allergic reaction may include: skin rash, swelling or itching of the face, lips, tongue or throat, or trouble breathing.heart failure. MAVENCLAD may cause heart failure, which means your heart may not pump as well as it should. Call your healthcare provider or go to the closest emergency room for medical help right away if you have any signs or symptoms such as shortness of breath, fast or irregular heart beat, or unusual swelling in your body.Your healthcare provider may delay or completely stop treatment with MAVENCLAD if you have severe side effects.The most common side effects of MAVENCLAD include:upper respiratory infectionheadachelow white blood cell countsThese are not all the possible side effects of MAVENCLAD. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store MAVENCLADMAVENCLAD comes in child resistant package.Store MAVENCLAD at room temperature between 68F and 77F (20C and 25C).Store MAVENCLAD in the original package to protect from moisture.Ask your healthcare provider or pharmacist about how to safely throw away any unused or expired MAVENCLAD tablets and packaging.Keep MAVENCLAD and all medicines out of the reach of children.General information about the safe and effective use of MAVENCLADMedicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use MAVENCLAD for condition for which it was not prescribed. Do not give MAVENCLAD to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider for information about MAVENCLAD that is written for health professionals.What are the ingredients in MAVENCLADActive ingredient: cladribineInactive ingredients: hydroxypropyl betadex, magnesium stearate, and sorbitol.Distributed by: EMD Serono, Inc., Rockland, MA 02370MAVENCLAD is registered trademark of Merck KGaA, Darmstadt, Germany.For more information, call toll-free1-877-447-3243 or go to www.mavenclad.com. Risk of cancer (malignancies). Treatment with MAVENCLAD may increase your risk of developing cancer. Talk to your healthcare provider about your risk of developing cancer if you receive MAVENCLAD. You should follow your healthcare provider instructions about screening for cancer.. MAVENCLAD may cause birth defects if used during pregnancy. Females must not be pregnant when they start treatment with MAVENCLAD or become pregnant during MAVENCLAD dosing and within months after the last dose of each yearly treatment course. Stop your treatment with MAVENCLAD and call your healthcare provider right away if you become pregnant during treatment with MAVENCLAD.For females who are able to become pregnant:Your healthcare provider should order pregnancy test for you before you begin your first and second yearly treatment course of MAVENCLAD to make sure that you are not pregnant. Your healthcare provider will decide when to do the test.Use effective birth control (contraception) on the days on which you take MAVENCLAD and for at least months after the last dose of each yearly treatment course.Talk to your healthcare provider if you use oral contraceptives (the pill).You should use second method of birth control on the days on which you take MAVENCLAD and for at least weeks after your last dose of each yearly treatment course. For males with female partners who are able to become pregnant:Use effective birth control (contraception) during the days on which you take MAVENCLAD and for at least months after the last dose of each yearly treatment course. For females who are able to become pregnant:Your healthcare provider should order pregnancy test for you before you begin your first and second yearly treatment course of MAVENCLAD to make sure that you are not pregnant. Your healthcare provider will decide when to do the test.Use effective birth control (contraception) on the days on which you take MAVENCLAD and for at least months after the last dose of each yearly treatment course.Talk to your healthcare provider if you use oral contraceptives (the pill).You should use second method of birth control on the days on which you take MAVENCLAD and for at least weeks after your last dose of each yearly treatment course. Your healthcare provider should order pregnancy test for you before you begin your first and second yearly treatment course of MAVENCLAD to make sure that you are not pregnant. Your healthcare provider will decide when to do the test.. Use effective birth control (contraception) on the days on which you take MAVENCLAD and for at least months after the last dose of each yearly treatment course.Talk to your healthcare provider if you use oral contraceptives (the pill).You should use second method of birth control on the days on which you take MAVENCLAD and for at least weeks after your last dose of each yearly treatment course. Talk to your healthcare provider if you use oral contraceptives (the pill).. You should use second method of birth control on the days on which you take MAVENCLAD and for at least weeks after your last dose of each yearly treatment course.. For males with female partners who are able to become pregnant:Use effective birth control (contraception) during the days on which you take MAVENCLAD and for at least months after the last dose of each yearly treatment course. Use effective birth control (contraception) during the days on which you take MAVENCLAD and for at least months after the last dose of each yearly treatment course.. have cancer (malignancy).. are pregnant, plan to become pregnant, or are woman of childbearing age or man able to father child and you are not using birth control. See What is the most important information should know about MAVENCLAD. are human immunodeficiency virus (HIV) positive.. have active infections, including tuberculosis (TB), hepatitis or C.. are allergic to cladribine.. are breastfeeding. See Before you take MAVENCLAD, tell your healthcare provider about all of your medical conditions, including if you:. think you have an infection.. have heart failure.. have liver or kidney problems.. have taken, take, or plan to take medicines that affect your immune system or your blood cells, or other treatments for MS. Certain medicines can increase your risk of getting an infection.. have had recent vaccination or are scheduled to receive any vaccinations. You should not receive live or live-attenuated vaccines within the to weeks preceding your treatment with MAVENCLAD. You should not receive these types of vaccines during your treatment with MAVENCLAD and until your healthcare provider tells you that your immune system is no longer weakened.. have or have had cancer.. are breastfeeding or plan to breastfeed. It is not known if MAVENCLAD passes into your breast milk. Do not breastfeed on the days, on which you take MAVENCLAD, and for 10 days after the last dose. See Do not take MAVENCLAD if you:. MAVENCLAD is given as two yearly treatment courses.. Each yearly treatment course consists of treatment weeks (also called cycles) that will be about month apart. Your healthcare provider will tell you when you have to start your treatment weeks and how many tablets per week you need, depending on your weight. Each treatment week is or days.. Your pharmacist will dispense carton of MAVENCLAD for each treatment week. The prescribed number of tablets per day are provided in child resistant day packs.. Take MAVENCLAD exactly as your healthcare provider tells you. Do not change your dose or stop taking MAVENCLAD unless your healthcare provider tells you to.. Take MAVENCLAD with water and swallow whole without chewing. MAVENCLAD can be taken with or without food.. Swallow MAVENCLAD right away after opening the blister pack.. Your hands must be dry when handling MAVENCLAD and washed well with water afterwards.. Limit contact with your skin. Avoid touching your nose, eyes and other parts of the body. If you get MAVENCLAD on your skin or on any surface, wash it right away with water.. Take MAVENCLAD at least hours apart from other medicines taken by mouth during the 4- to 5-day MAVENCLAD treatment week.. If you miss dose, take it as soon as you remember on the same day. If the whole day passes before you remember, take your missed dose the next day. Do not take doses at the same time. Instead, you will extend the number of days in that treatment week.. See What is the most important information should know about MAVENCLAD low blood cell counts. Low blood cell counts have happened and can increase your risk of infections during your treatment with MAVENCLAD. Your healthcare provider will do blood tests before you start treatment with MAVENCLAD, during your treatment with MAVENCLAD, and afterward, as needed.. serious infections such as:TB, hepatitis or C, and shingles (herpes zoster). Fatal cases of TB and hepatitis have happened with cladribine during clinical studies. Tell your healthcare provider right away if you get any symptoms of the following infection related problems or if any of the symptoms get worse, including:. TB, hepatitis or C, and shingles (herpes zoster). Fatal cases of TB and hepatitis have happened with cladribine during clinical studies. Tell your healthcare provider right away if you get any symptoms of the following infection related problems or if any of the symptoms get worse, including:. fever. aching painful muscles. headache. feeling of being generally unwell. loss of appetite. burning, tingling, numbness or itchiness of the skin in the affected area. skin blotches, blistered rash and severe pain. progressive multifocal leukoencephalopathy (PML). PML is rare brain infection that usually leads to death or severe disability. Although PML has not been seen in MS patients taking MAVENCLAD, it may happen in people with weakened immune systems. Symptoms of PML get worse over days to weeks. Call your healthcare provider right away if you have any new or worsening neurologic signs or symptoms of PML, that have lasted several days, including:. weakness on side of your body. loss of coordination in your arms and legs. decreased strength. problems with balance. changes in your vision. changes in your thinking or memory. confusion. changes in your personality. liver problems. MAVENCLAD may cause liver problems. Your healthcare provider should do blood tests to check your liver before you start taking MAVENCLAD. Call your healthcare provider right away if you have any of the following symptoms of liver problems:. nausea. vomiting. stomach pain. tiredness. loss of appetite. your skin or the whites or your eyes turn yellow. dark urine. allergic reactions (hypersensitivities). MAVENCLAD can cause serious allergic reactions. Stop your treatment with MAVENCLAD and go to the closest emergency room for medical help right away if you have any signs or symptoms of allergic reactions. Symptoms of an allergic reaction may include: skin rash, swelling or itching of the face, lips, tongue or throat, or trouble breathing.. heart failure. MAVENCLAD may cause heart failure, which means your heart may not pump as well as it should. Call your healthcare provider or go to the closest emergency room for medical help right away if you have any signs or symptoms such as shortness of breath, fast or irregular heart beat, or unusual swelling in your body.. upper respiratory infection. headache. low white blood cell counts. MAVENCLAD comes in child resistant package.. Store MAVENCLAD at room temperature between 68F and 77F (20C and 25C).. Store MAVENCLAD in the original package to protect from moisture.. Ask your healthcare provider or pharmacist about how to safely throw away any unused or expired MAVENCLAD tablets and packaging.

SPL UNCLASSIFIED SECTION.

oMalignancies Treatment with MAVENCLAD may increase the risk of malignancy. MAVENCLAD is contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of MAVENCLAD on an individual patient basis. Follow standard cancer screening guidelines in patients treated with MAVENCLAD [see Contraindications (4) and Warnings and Precautions (5.1)].

STORAGE AND HANDLING SECTION.

16.2Storage and Handling. Store at controlled room temperature, 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. Store in original package in order to protect from moisture.MAVENCLAD is cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryMAVENCLAD is contraindicated in pregnant women and in females and males of reproductive potential who do not plan to use effective contraception. There are no adequate data on the developmental risk associated with use of MAVENCLAD in pregnant women. Cladribine was embryolethal when administered to pregnant mice and produced malformations in mice and rabbits [see Data]. The observed developmental effects are consistent with the effects of cladribine on DNA [see Contraindications (4) and Warnings and Precautions (5.2)]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.. Data. Animal DataWhen cladribine was administered intravenously (0, 0.5, 1.5, or mg/kg/day) to pregnant mice during the period of organogenesis, fetal growth retardation and malformations (including exencephaly and cleft palate) and embryofetal death were observed at the highest dose tested. An increase in skeletal variations was observed at all but the lowest dose tested. There was no evidence of maternal toxicity.When cladribine was administered intravenously (0, 0.3, 1, and mg/kg/day) to pregnant rabbits during the period of organogenesis, fetal growth retardation and high incidence of craniofacial and limb malformations were observed at the highest dose tested, in the absence of maternal toxicity.When cladribine was administered intravenously (0, 0.5, 1.5, or 3.0 mg/kg/day) to mice throughout pregnancy and lactation, skeletal anomalies and embryolethality were observed at all but the lowest dose tested.. 8.2 Lactation. Risk SummaryMAVENCLAD is contraindicated in breastfeeding women because of the potential for serious adverse reactions in breastfed infants [see Contraindications (4) and Warnings and Precautions (5)]. Advise women not to breastfeed during dosing with MAVENCLAD and for 10 days after the last dose.There are no data on the presence of cladribine in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingIn females of reproductive potential, pregnancy should be excluded before the initiation of each treatment course of MAVENCLAD [see Use in Specific Populations (8.1)]. Contraception. FemalesFemales of reproductive potential should prevent pregnancy by use of effective contraception during MAVENCLAD dosing and for at least months after the last dose in each treatment course. It is unknown if MAVENCLAD may reduce the effectiveness of the systemically acting hormonal contraceptives. Women using systemically acting hormonal contraceptives should add barrier method during MAVENCLAD dosing and for at least weeks after the last dose in each treatment course. Women who become pregnant during MAVENCLAD therapy should discontinue treatment [see Warnings and Precautions (5.2) and Drug Interactions (7.7)]. MalesAs cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected. Therefore, male patients of reproductive potential should take precautions to prevent pregnancy of their partner during MAVENCLAD dosing and for at least months after the last dose in each treatment course [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. The safety and effectiveness in pediatric patients (below 18 years of age) have not been established. Use of MAVENCLAD is not recommended in pediatric patients because of the risk of malignancies [see Warnings and Precautions (5.1)]. 8.5 Geriatric Use. Clinical studies with MAVENCLAD did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution is recommended when MAVENCLAD is used in elderly patients, taking into account the potential greater frequency of decreased hepatic, renal, or cardiac function, concomitant diseases, and other drug therapy.. 8.6Patients with Renal Impairment. The concentration of cladribine is predicted to increase in patients with renal impairment [see Clinical Pharmacology (12.3)]. No dosage adjustment is recommended in patients with mild renal impairment (creatinine clearance 60 to 89 mL per minute). MAVENCLAD is not recommended in patients with moderate to severe renal impairment (creatinine clearance below 60 mL per minute) [see Clinical Pharmacology (12.3)]. 8.7Patients with Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics of cladribine is unknown [see Clinical Pharmacology (12.3)]. No dosage adjustment is recommended in patients with mild hepatic impairment. MAVENCLAD is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh score greater than 6) [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Lymphopenia: Monitor lymphocyte counts before, during and after treatment. (5.3)Infections: Screen patients for latent infections; consider delaying treatment until infection is fully controlled. Vaccinate patients antibody-negative to varicella zoster virus prior to treatment. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections. (5.4)Hematologic toxicity: Monitor complete blood count before, during and after treatment. (5.5)Graft-versus-host-disease with blood transfusion: Irradiation of cellular blood components is recommended. (5.6)Liver injury: Obtain tests prior to treatment. Discontinue if clinically significant injury is suspected. (5.7). Lymphopenia: Monitor lymphocyte counts before, during and after treatment. (5.3). Infections: Screen patients for latent infections; consider delaying treatment until infection is fully controlled. Vaccinate patients antibody-negative to varicella zoster virus prior to treatment. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections. (5.4). Hematologic toxicity: Monitor complete blood count before, during and after treatment. (5.5). Graft-versus-host-disease with blood transfusion: Irradiation of cellular blood components is recommended. (5.6). Liver injury: Obtain tests prior to treatment. Discontinue if clinically significant injury is suspected. (5.7). 5.1Malignancies. Treatment with MAVENCLAD may increase the risk of malignancy. In controlled and extension clinical studies worldwide, malignancies occurred more frequently in MAVENCLAD-treated patients [10 events in 3,754 patient-years (0.27 events per 100 patient-years)], compared to placebo patients [3 events in 2,275 patient-years (0.13 events per 100 patient-years)]. Malignancy cases in MAVENCLAD patients included metastatic pancreatic carcinoma, malignant melanoma (2 cases), ovarian cancer, compared to malignancy cases in placebo patients, all of which were curable by surgical resection [basal cell carcinoma, cervical carcinoma in situ (2 cases)]. The incidence of malignancies in United States MAVENCLAD clinical study patients was higher than the rest of the world [4 events in 189 patient-years (2.21 events per 100 patient-years) compared to events in United States placebo patients]; however, the United States results were based on limited amount of patient data.After the completion of treatment courses, do not administer additional MAVENCLAD treatment during the next years [see Dosage and Administration (2.2)]. In clinical studies, patients who received additional MAVENCLAD treatment within years after the first treatment courses had an increased incidence of malignancy [7 events in 790 patient-years (0.91 events per 100 patient-years) calculated from the start of cladribine treatment in Year 3]. The risk of malignancy with reinitiating MAVENCLAD more than years after the completion of treatment courses has not been studied.MAVENCLAD is contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of MAVENCLAD on an individual patient basis. Follow standard cancer screening guidelines in patients treated with MAVENCLAD.. 5.2Risk of Teratogenicity. MAVENCLAD may cause fetal harm when administered to pregnant women. Malformations and embryolethality occurred in animals [see Use in Specific Populations (8.1)]. Advise women of the potential risk to fetus during MAVENCLAD dosing and for months after the last dose in each treatment course.In females of reproductive potential, pregnancy should be excluded before initiation of each treatment course of MAVENCLAD and prevented by the use of effective contraception during MAVENCLAD dosing and for at least months after the last dose of each treatment course. Women who become pregnant during treatment with MAVENCLAD should discontinue treatment [see Use in Specific Populations (8.1, 8.3)]. MAVENCLAD is contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception.. 5.3Lymphopenia. MAVENCLAD causes dose-dependent reduction in lymphocyte count. In clinical studies, 87% of MAVENCLAD-treated patients experienced lymphopenia. The lowest absolute lymphocyte counts occurred approximately to months after the start of each treatment course and were lower with each additional treatment course. In patients treated with cumulative dose of MAVENCLAD 3.5 mg per kg over courses as monotherapy, 26% and 1% had nadir absolute lymphocyte counts less than 500 and less than 200 cells per microliter, respectively. At the end of the second treatment course, 2% of clinical study patients had lymphocyte counts less than 500 cells per microliter; median time to recovery to at least 800 cells per microliter was approximately 28 weeks.Additive hematological adverse reactions may be expected if MAVENCLAD is administered prior to or concomitantly with other drugs that affect the hematological profile [see Drug Interactions (7.3)]. The incidence of lymphopenia less than 500 cells per microliter was higher in patients who had used drugs to treat relapsing forms of MS prior to study entry (32.1%), compared to those with no prior use of these drugs (23.8%).Obtain complete blood count (CBC) with differential including lymphocyte count prior to, during, and after treatment with MAVENCLAD. See Dosage and Administration (2.1, 2.5) and Warnings and Precautions (5.4) for timing of CBC measurements and additional instructions based on the patients lymphocyte counts and clinical status (e.g., infections).. 5.4Infections. MAVENCLAD can reduce the bodys immune defense and may increase the likelihood of infections. Infections occurred in 49% of MAVENCLAD-treated patients compared to 44% of placebo patients in clinical studies. The most frequent serious infections in MAVENCLAD-treated patients included herpes zoster and pyelonephritis (see Herpes Virus Infections). Fungal infections were observed, including cases of coccidioidomycosis.HIV infection, active tuberculosis, and active hepatitis must be excluded before initiation of each treatment course of MAVENCLAD [see Contraindications (4)]. Consider delay in initiation of MAVENCLAD in patients with an acute infection until the infection is fully controlled.Initiation of MAVENCLAD in patients currently receiving immunosuppressive or myelosuppressive therapy is not recommended [see Drug Interactions (7.1)]. Concomitant use of MAVENCLAD with these therapies could increase the risk of immunosuppression.. TuberculosisThree of 1,976 (0.2%) cladribine-treated patients in the clinical program developed tuberculosis. All three cases occurred in regions where tuberculosis is endemic. One case of tuberculosis was fatal, and two cases resolved with treatment.Perform tuberculosis screening prior to initiation of the first and second treatment course of MAVENCLAD. Latent tuberculosis infections may be activated with use of MAVENCLAD. In patients with tuberculosis infection, delay initiation of MAVENCLAD until the infection has been adequately treated.. HepatitisOne clinical study patient died from fulminant hepatitis infection. Perform screening for hepatitis and prior to initiation of the first and second treatment course of MAVENCLAD. Latent hepatitis infections may be activated with use of MAVENCLAD. Patients who are carriers of hepatitis or virus may be at risk of irreversible liver damage caused by virus reactivation. In patients with hepatitis infection, delay initiation of MAVENCLAD until the infection has been adequately treated.. Herpes Virus InfectionsIn controlled clinical studies, 6% of MAVENCLAD-treated patients developed herpes viral infection compared to 2% of placebo patients. The most frequent types of herpes viral infections were herpes zoster infections (2.0% vs. 0.2%) and oral herpes (2.6% vs. 1.2%). Serious herpes zoster infections occurred in 0.2% of MAVENCLAD-treated patients.Vaccination of patients who are antibody-negative for varicella zoster virus is recommended prior to initiation of MAVENCLAD. Administer live-attenuated or live vaccines at least to weeks prior to starting MAVENCLAD.The incidence of herpes zoster was higher during the period of absolute lymphocyte count less than 500 cells per microliter, compared to the time when the patients were not experiencing this degree of lymphopenia. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Patients with lymphocyte counts below 500 cells per microliter should be monitored for signs and symptoms suggestive of infections, including herpes infections. If such signs and symptoms occur, initiate treatment as clinically indicated. Consider interruption or delay of MAVENCLAD until resolution of the infection.. Progressive Multifocal LeukoencephalopathyProgressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.No case of PML has been reported in clinical studies of cladribine in patients with multiple sclerosis. In patients treated with parenteral cladribine for oncologic indications, cases of PML have been reported in the postmarketing setting.Obtain baseline (within months) magnetic resonance imaging (MRI) before initiating the first treatment course of MAVENCLAD. At the first sign or symptom suggestive of PML, withhold MAVENCLAD and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms.. VaccinationsAdminister all immunizations according to immunization guidelines prior to starting MAVENCLAD. Administer live-attenuated or live vaccines at least to weeks prior to starting MAVENCLAD, because of risk of active vaccine infection (see Herpes Virus Infections). Avoid vaccination with live-attenuated or live vaccines during and after MAVENCLAD treatment while the patients white blood cell counts are not within normal limits. 5.5Hematologic Toxicity. In addition to lymphopenia [see Warnings and Precautions (5.3)], decreases in other blood cells and hematological parameters have been reported with MAVENCLAD in clinical studies. Mild to moderate decreases in neutrophil counts (cell count between 1,000 cells per microliter and lower limit of normal (LLN)) were observed in 27% of MAVENCLAD-treated patients, compared to 13% of placebo patients whereas severe decreases in neutrophil counts (cell count below 1,000 cells per microliter) were observed in 3.6% of MAVENCLAD-treated patients, compared to 2.8% of placebo patients. Decreases in hemoglobin levels, in general mild to moderate (hemoglobin 8.0 per dL to LLN), were observed in 26% of MAVENCLAD-treated patients, compared to 19% of placebo patients. Decreases in platelet counts were generally mild (cell count 75,000 cells per microliter to LLN) and were observed in 11% of MAVENCLAD-treated patients, compared to 4% of placebo patients.In clinical studies at dosages similar to or higher than the approved MAVENCLAD dosage, serious cases of thrombocytopenia, neutropenia, and pancytopenia (some with documented bone marrow hypoplasia) requiring transfusion and granulocyte-colony stimulating factor treatment have been reported [see Warnings and Precautions (5.6) for information regarding graft-versus-host disease with blood transfusion].Obtain complete blood count (CBC) with differential prior to, during, and after treatment with MAVENCLAD [see Dosage and Administration (2.1, 2.5)]. 5.6Graft-Versus-Host Disease With Blood Transfusion. Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of nonirradiated blood in patients treated with cladribine for non-MS treatment indications.In patients who require blood transfusion, irradiation of cellular blood components is recommended prior to administration to decrease the risk of transfusion-related graft-versus-host disease. Consultation with hematologist is advised.. 5.7Liver Injury. In clinical studies, 0.3% of MAVENCLAD-treated patients had liver injury (serious or causing treatment discontinuation) considered related to treatment, compared to placebo patients. Onset has ranged from few weeks to several months after initiation of treatment with MAVENCLAD. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 20-fold the upper limit of normal, have been observed. These abnormalities resolved upon treatment discontinuation.Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to the first and second treatment course [see Dosage and Administration (2.1)]. If patient develops clinical signs, including unexplained liver enzyme elevations or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with MAVENCLAD, as appropriate.. 5.8Hypersensitivity. In clinical studies, 11% of MAVENCLAD-treated patients had hypersensitivity reactions, compared to 7% of placebo patients. Hypersensitivity reactions that were serious and/or led to discontinuation of MAVENCLAD (e.g., dermatitis, pruritis) occurred in 0.5% of MAVENCLAD-treated patients, compared to 0.1% of placebo patients. One patient had serious hypersensitivity reaction with rash, mucous membrane ulceration, throat swelling, vertigo, diplopia, and headache after the first dose of MAVENCLAD.If hypersensitivity reaction is suspected, discontinue MAVENCLAD therapy. Do not use MAVENCLAD in patients with history of hypersensitivity to cladribine [see Contraindications (4)]. 5.9Cardiac Failure. In clinical studies, one MAVENCLAD-treated patient experienced life-threatening acute cardiac failure with myocarditis, which improved after approximately one week. Cases of cardiac failure have also been reported with parenteral cladribine used for treatment indications other than multiple sclerosis.Instruct patients to seek medical advice if they experience symptoms of cardiac failure (e.g., shortness of breath, rapid or irregular heartbeat, swelling).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.In the clinical trial program of cladribine in MS, 1,976 patients received cladribine for total of 9,509 patient years. The mean time on study including follow-up was approximately 4.8 years, and approximately 24% of cladribine-treated patients had approximately years of time on study including follow-up. Of these, 923 patients aged 18 to 66 years received MAVENCLAD as monotherapy at cumulative dose of 3.5 mg per kg.Table shows adverse reactions in Study [see Clinical Studies (14)] with an incidence of at least 5% for MAVENCLAD and higher than placebo. The most common (> 20%) adverse reactions reported in Study are upper respiratory tract infection, headache, and lymphopenia.Table 2Adverse Reactions in Study with an Incidence of at Least 5% for MAVENCLAD and Higher than PlaceboMAVENCLAD(N=440)%Placebo(N=435)%Upper respiratory tract infection3832Headache2519Lymphopenia242Nausea109Back pain86Arthralgia and arthritis75Insomnia64Bronchitis53Hypertension53Fever53Depression53. HypersensitivityIn clinical studies, 11% of MAVENCLAD patients had hypersensitivity adverse reactions, compared to 7% of placebo patients [see Warnings and Precautions (5.8)]. AlopeciaAlopecia occurred in 3% of MAVENCLAD-treated patients compared to 1% of placebo patients.. Myelodysplastic SyndromeCases of myelodysplastic syndrome have been reported in patients that had received parenteral cladribine at higher dosage than that approved for MAVENCLAD. These cases occurred several years after treatment.. Herpes MeningoencephalitisFatal herpes meningoencephalitis occurred in one MAVENCLAD-treated patient, at higher dosage and longer duration of therapy than the approved MAVENCLAD dosage and in combination with interferon beta-1a treatment.. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)SJS and TEN are identified risks of parenteral cladribine for the treatment of oncologic indications.. SeizuresIn clinical studies, serious events of seizure occurred in 0.3% of MAVENCLAD-treated patients compared to placebo patients. Serious events included generalized tonic-clonic seizures and status epilepticus. It is unknown whether these events were related to the effects of multiple sclerosis alone, to MAVENCLAD, or to combination of both.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.1)9/2022Warnings and Precautions (5.4)9/2022.